Although it is well documented that serotonin (5-HT) enhances the secretion of prolactin (PRL) from the anterior pituitary gland, little progress has been made in elucidating the mechanism of action of 5-HT in this regard or factors that modulate the PRL response to 5-HT like agents. We have found that repeated administration of the indole hallucinogen, 5-methoxy-N,N-dimethyltryptamine (5MeODMT, 5 mg/kg every 3 hrs for a total of 4 injections) or other related substances potentiates the PRL releasing effect of a number of 5-HT agonists. On the other hand, a single injection of 5MeODMT causes a diminished PRL response (acute tolerance or agonist induced antagonism) to the subsequent administration of 5-HT agonists. It is our intention to investigate the extent to which, and mechanisms by which, modulation of the frequency of 5-HT agonist administration alters the responsiveness of PRL secreting mechanisms or 5-HT receptor sensitivity. The apparent sensitivity of 5-HT receptors is also enhanced after chronic lithium treatment, as the PRL responses to 5-HT agonists is potentiated in lithium-treated rats. One objective is to determine whether the enhanced PRL response following repeated administration of 5MeODMT or lithium reflects a state of supersensitivity of 5-HT receptors in the CNS or a state of enhanced responsiveness of the anterior pituitary gland. The effect of these treatments on the concentration and turnover of 5-HT in the hypothalamus will be examined. In order to investigate possible alterations in central 5-HT receptors, the effect of repeated 5MeODMT injections and lithium on brain membrane binding of 3H-5HT and 3H-spiperone will be studied in vitro. Since an increased PRL response to 5-HT agonists might result from diminished dopaminergic activity in tuberoinfundibular neurons, dopamine concentrations in hypohysial portal plasma will be measured, and the sensitivity of the pituitary gland to the inhibitory effect of dopamine on PRL secretion will be assessed. We also propose to investigate the role of pre- and postsynaptic 5-HT receptors and their interaction with the dopamine system in the development of the 5MeODMT-induced acute tolerance or agonist-induced antagonism to the PRL releasing effect of 5-HT agonists. Results from these studies will enable us to better understand the roles of 5-HT neuronal activity and altered receptor sensitivity in the regulation of PRL secretion.